RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition

Carolina Nunes, Lisa Depestel, Liselot Mus, Kaylee M. Keller, Louis Delhaye, Amber Louwagie, Muhammad Rishfi, Alex Whale, Neesha Kara, Simon R. Andrews, Filemon Dela Cruz, Daoqi You, Armaan Siddiquee, Camila Takeno Cologna, Sam De Craemer, Emmy Dolman, Christoph Bartenhagen, Fanny De Vloed, Ellen Sanders, Aline EggermontSarah Lee Bekaert, Wouter Van Loocke, Jan Willem Bek, Givani Dewyn, Siebe Loontiens, Gert Van Isterdael, Bieke Decaesteker, Laurentijn Tilleman, Filip Van Nieuwerburgh, Vanessa Vermeirssen, Christophe Van Neste, Bart Ghesquiere, Steven Goossens, Sven Eyckerman, Katleen De Preter, Matthias Fischer, Jon Houseley, Jan Molenaar, Bram De Wilde, Stephen S. Roberts, Kaat Durinck, Frank Speleman

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

2 Citaten (Scopus)

Samenvatting

High-risk neuroblastoma, a pediatric tumor originating from the sympathetic nervous system, has a low mutation load but highly recurrent somatic DNA copy number variants. Previously, segmental gains and/or amplifications allowed identification of drivers for neuroblastoma development. Using this approach, combined with gene dosage impact on expression and survival, we identified ribonucleotide reductase subunit M2 (RRM2) as a candidate dependency factor further supported by growth inhibition upon in vitro knockdown and accelerated tumor formation in a neuroblastoma zebrafish model coexpressing human RRM2 with MYCN. Forced RRM2 induction alleviates excessive replicative stress induced by CHK1 inhibition, while high RRM2 expression in human neuroblastomas correlates with high CHK1 activity. MYCN-driven zebrafish tumors with RRM2 co-overexpression exhibit differentially expressed DNA repair genes in keeping with enhanced ATR-CHK1 signaling activity. In vitro, RRM2 inhibition enhances intrinsic replication stress checkpoint addiction. Last, combinatorial RRM2-CHK1 inhibition acts synergistic in high-risk neuroblastoma cell lines and patient-derived xenograft models, illustrating the therapeutic potential.

Originele taal-2Engels
Artikelnummereabn1382
TijdschriftScience Advances
Volume8
Nummer van het tijdschrift28
DOI's
StatusGepubliceerd - jul. 2022

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